Sarcopenia is associated with survival in patients awaiting kidney transplant.

BACKGROUND: The relationship of sarcopenia to frailty and other survival determinants in patients waitlisted for kidney transplant is not well characterized. Our goal was to evaluate the relationship of muscle area to functional and frailty metrics and its impact on survival in patients waitlisted for kidney transplant. METHODS: Among 303 consecutively listed transplant candidates, 172 had a computed scan within 3 months of frailty and biochemical testing that permitted muscle area evaluation. Third lumbar level psoas muscle indices (total bilateral psoas area/height2) were calculated. Testing included frailty metrics, treadmill and pedometer ability, troponin, and brain natriuretic peptide levels. Associations between muscle area, demographic, biochemical, and frailty measures were analyzed. Log-rank test was used to evaluate waitlist survival on the basis of muscle area, and multivariate Cox proportional hazards modeling was used to evaluate factors independently associated with survival. RESULTS: Demographic factors associated with third lumbar level psoas muscle indices include male sex (P < .001), race (P = .02), age (P = .004), and body mass index (P < .0001). Grip strength, treadmill ability, and Sit-Stands positively correlated with third lumbar level psoas muscle indices (P < .01). Brain natriuretic peptide and Up and Go negatively correlated with third lumbar level psoas muscle indices (P < .01). Survival was significantly associated with third lumbar level psoas muscle indices (P = 0.02). Treadmill ability, Sit-Stands, Up and Go, race and muscle area were most closely associated with waitlist survival on multivariate modeling. CONCLUSION: Sarcopenia as assessed with muscle area measurements is independently associated with kidney waitlist survival. Functional ability and muscle area may be overlapping, but noncongruent, determinants of waitlist outcomes and may need to be individually assessed to create the most predictive survival model.

Does the Surgical Approach Affect the Incidence of Post-Hepatectomy Liver Failure in Cirrhotic Patients? An Analysis of the NSQIP Database.

Background: The association between surgical approach and post-hepatectomy liver failure (PHLF) in cirrhotic patients is poorly understood. We hypothesize that patients will have similar rates of liver failure regardless of whether they undergo minimally invasive liver resection (MILR) or open liver resection (OLR) in major liver resections. In contrast, there will be lower rates of PHLF in patients undergoing minor hepatectomy via the MILR approach.Methods: Propensity score matching was used to analyze regression by matching the MILR to the OLR cohort. Patient demographics from the American College of Surgeons National Surgical Quality Improvement Program, including race, age, gender, and ethnicity, were matched. Chronic obstructive pulmonary disease, congestive heart failure, smoking, hypertension, diabetes, renal failure, dyspnea, dialysis dependence, body mass index, and American Society of Anesthesiologists (ASA) classification (>ASA III) were among the preoperative patient characteristics subject to matching. PHLF (Grade A vs B. vs C) was our primary outcome measure.Results: A total of 2129 cirrhotic patients were included in the study. In the minor hepatectomy group, patients undergoing an OLR were more likely to get discharged to a facility (7.0% vs 4.4%; P = .03), had greater hospital length of stay (5 vs 3 days; P = .02), and had a greater need for invasive postoperative interventions (10.7% vs 4.6%; P < .01). They were also noted to have higher rates of organ space superficial surgical infections (SSIs) (7.3% vs 3.7%; P = .003), Clostridium difficile infection (.9% vs .1%; P = .05), renal insufficiency (2.1% vs .1%; P < .01), unplanned intubations (3.1% vs 1.4%; P = .03), and Grade C liver failure (2.3% vs .9%; P = .03).Conclusion: A higher incidence of PHLF grade C was found in patients undergoing OLR in the minor hepatectomy group. Therefore, in cirrhotic patients who can tolerate minimally invasive approaches, MILR should be offered to prevent postoperative complications as part of their optimization plan.

Liver transplant versus liver resection in patients with multifocal hepatocellular carcinoma.

BACKGROUND: The optimal surgical option in patients with multifocal hepatocellular carcinoma (MHCC) is an area of active research. The preference varies based on geographic variations and institutional policies. We sought to determine long-term outcomes in patients with MHCC based on surgical treatment-liver transplant (LT) vs resection (LR). METHODS: We performed a retrospective analysis of the National Cancer Database (2004-2015) and identified patients with MHCC within Milan criteria. Patients with α-fetoprotein ≥ 1000 ng/mL and those who underwent ablation were excluded. The primary outcome measure was long-term survival in patients undergoing LT vs LR. The secondary aim of our study was to determine clinicodemographic factors associated with the receipt of LT and LR. RESULTS: A total of 1546 patients were included, of whom 1211 received LT and 335 underwent LR. Patients who were non-Hispanic White (70.8% vs 54.9%; P < .01), privately insured (53.7% vs 36.7%; P < .01), and treated at academic centers (85.4% vs 71.6%; P < .01) were more likely to receive an LT. Multivariable Cox analysis revealed LT was associated with improved survival compared with LR (hazard ratio, 0.34; 95% CI, 0.28-0.42). CONCLUSION: We described clinical and sociodemographic differences in LT and LR patients and found LT to be associated with a decreased mortality risk compared with LR. The study's findings should be interpreted in the context of several limitations, including the selection of MHCC criteria within Milan criteria.

Liver resection is superior to tumor ablation in patients with multifocal hepatocellular carcinoma.

INTRODUCTION: The management of T2 multifocal hepatocellular carcinoma (MHCC) is controversial, and the comparative impact of liver resection (LR) versus tumor ablation (TA) on survival continues to be debated. The aim of our study was to examine short- and long-term survival for LR and TA in a nationally representative cohort. We hypothesized that patients who underwent LR would have improved survival. METHODS: We utilized the National Cancer Database (2004-2015) to identify patients diagnosed with non-metastatic T2 MHCC. Kaplan-Meier survival curves were generated to compare 10-year overall survival (OS) between LR and TA patients. Kaplan-Meier analysis with stratification was also performed based on lymphovascular invasion, resection margin status, and Charlson-Deyo score. Cox proportional hazard models were used in multivariable analyses. RESULTS: A total of 1225 patients met the inclusion criteria. 991 patients received LR, and 234 received TA. The majority of patients were male, White, and older than ≥60 years old. Clinicodemographic characteristics were generally similar between LR and TA patients. Among patients who underwent LR, 84% had negative margins, and 17% had lymphovascular invasion. Mortality at 30 days was significantly higher among LR patients compared to TA patients (5.4% vs 0.0%, p < 0.001), with those having a Charlson-Deyo score ≥2 facing the highest risk at 7.3%. Nevertheless, 10-year OS for the LR cohort was 27.5% (95% confidence interval [CI]: 24.4%-30.8%) versus 14.7% (95% CI: 9.8%-20.7%, p < 0.001) for TA patients. In stratified analysis, survival benefit was statistically significant only among those with negative resection margin, no lymphovascular invasion, and Charlson-Deyo score ≤1. In multivariable Cox analysis, LR was independently associated with improved survival compared to TA (hazard ratio: 0.80; 95% CI = 0.67-0.95). CONCLUSION: LR poses a higher long-term survival benefit than TA. Prospective studies are warranted to confirm these findings. Although our study patients are a highly selected group of multifocal T2 patients, it gives us a good insight into the fact that LR provides better outcomes if a transplant option is unavailable.

Trends and disparities in access to minimally invasive distal pancreatectomy (midp): an eight-year analysis from the national cancer database.

Laparoscopic and robotic approaches to distal pancreatectomy are becoming the standard of care. The aim of our study was to evaluate the trends of utilization and disparities in access to minimally invasive approaches in distal pancreatectomy. We queried the National Cancer Database (NCDB) and analyzed all the patients who underwent distal pancreatectomy from 2010 to 2017. Patients were divided into groups of those with open distal pancreatectomy (ODP) and those with laparoscopic or robotic distal pancreatectomy (MIDP = minimally invasive distal pancreatectomy). Our outcome measures were trends of MIDP and disparities in access to MIDP. Cochran Armitage trend analysis and multivariate regression analysis were used to evaluate outcomes. A total of 13,537 patients with distal pancreatectomy were identified in the NCDB from 2010 to 2017. 7548 (55.8%) underwent ODP, while 5989 (44.2%) underwent MIDP. The MIDP rates increased from 25% in 2010 to 52% in 2017 (p < 0.01). On regression analysis, when controlled for age, gender, diagnosis, tumor size, grade, staging, and chemoradiotherapy, African American patients were 30% less likely to undergo MIDP than White (OR 0.7, 95% CI [0.5-0.8], p < 0.01). Similarly, Hispanic patients were 25% less likely to undergo MIDP than non-Hispanic patients OR 0.75, 95% CI [0.6-0.9], p = 0.02). Compared to Medicare/private insured patients, uninsured patients were 50% less likely to undergo MIDP (OR 0.5, 95% CI [0.4-0.7], p < 0.01). Based on the medium household income, compared to patients in the fourth quartile, patients in the third quartile OR 0.9, 95% CI [0.3-0.9], p = 0.03). Second OR 0.8, 95%CI [0.5-0.9], p < 0.01), first quartile OR 0.7, 95% CI [0.5-0.8], p < 0.01) were less likely to undergo MIPD as well. Utilization of MIDP has increased from one in every four patients in 2010 to every other patient in 2017. However, African Americans, Hispanics, the uninsured, and those from low-income quartiles are less likely to undergo MIDP. Efforts should be made to ensure access to minimally invasive approches are available to minorities.

Outcomes in elderly patients undergoing hepatic resection compared to liver transplant for hepatocellular carcinoma.

BACKGROUND: Hepatic resection (HR) is an excellent option for patients with hepatocellular carcinoma (HCC). For patients meeting the Milan criteria, a liver transplant (LT) is also a viable option for patients with HCC, especially those with end-stage liver disease. With increasing rates of LTs amongst the elderly, we sought to determine long-term outcomes in patients who underwent HR compared to LTs in this patient population. METHODS: We queried the national cancer database for elderly patients (≥70 years) diagnosed with HCC between 2004 and 2020. The primary outcome was overall survival (OS) computed using the Kaplan-Meier method and Cox proportional hazard regression. One-to-one propensity score matching was conducted on the basis of clinicodemographic features to account for baseline differences between patients undergoing each procedure. RESULTS: Of the 5090 patients included, 4674 (91.8%) and 416 (8.2%) patients underwent HR and LT, respectively. Compared with HR patients, patients receiving LT had better OS (p < 0.001) and greater median survival time (65.6 months HR vs. 97.9 months LT, p < 0.001). On multivariable analysis, a LT was independently associated with improved survival (adjusted hazard ratio: 0.61, 95% confidence interval: 0.50-0.76, p < 0.001). CONCLUSIONS: LT is associated with improved survival for well-selected elderly patients with HCC. Age alone should not be used as the sole parameter for the candidacy of LT in elderly patients.

Outcomes after lung resection in renal transplant patients with pulmonary mucormycosis.

BACKGROUND: Pulmonary mucormycosis has been associated with high mortality (reported up to 100%) in renal transplant recipients. METHODS: This was a retrospective analysis of renal transplant patients with pulmonary mucormycosis between April 2014 and March 2020, who underwent surgical resection of the affected lung along with liposomal amphotericin therapy. Patients with lower respiratory illness features underwent chest X-ray, high-resolution computed tomography of the chest, and those with suspicious findings underwent analysis of bronchioloalveolar fluid and transbronchial lung biopsy. Patients with histological or microbiological evidence of mucormycosis were started on liposomal Amphotericin B. Tacrolimus and mycophenolate mofetil were stopped at the time of diagnosis. RESULT: Ten patients underwent combined management, while five patients were managed medically. At last follow up, seven out of ten patients (70%) who underwent combined management and two of the five patients (40%) who were managed medically, had a mean survival of 28.86 months (sd = 15.71, median = 25) and 14.17 months (sd = 12.21, median = 18), respectively, post-diagnosis of pulmonary mucormycosis. CONCLUSION: Surgical resection combined with antifungals in the perioperative period and decreased immunosuppression may improve the outcomes in renal transplant patients with pulmonary mucormycosis.

Experience With 15 Years of Laparoscopic Donor Nephrectomy: Review of 2500 Cases.

BACKGROUND: Laparoscopic donor nephrectomy (LDN) is considered the gold standard for live donor nephrectomies owing to lesser pain, shorter hospitalization, and earlier return to normal activities, yet it remains a technically challenging surgery. Repetition of a highly skilled task such as LDN should lead to improved performance reflected in shorter surgery times and a decrease in adverse events. METHODS: The records of over 2524 LDNs from February 2004 to June 2019 were evaluated for duration of surgery (from incision time to clamping of the renal artery) and occurrence of complications. RESULTS: The mean duration of surgery ± SD from incision to clamp time for the first 100 cases at the inception of LDN was 166.13 ± 33.28 minutes whereas it was 124.59 ± 35.91 minutes for the best 100 consecutive cases in 2015 with a decrease of 41 minutes duration of surgery from incision to artery clamping. The adverse events were accessory renal artery injury (n = 10), splenic laceration (n = 2), bowel and mesocolon injuries (n = 12), venous or arterial clip slippage (n = 4), inferior vena cava tear (n = 2) pneumothorax (during stapler application, n = 1), missing gauze counts (n = 1), chylous ascites (n = 1), ureteric thermal injury (n = 2), and renal parenchyma injury (n = 3). CONCLUSIONS: LDN is a technically demanding surgery where surgeon experience appears to affect operative metrics such as operative time. The occurrence of intraoperative complications appears to be acceptably low, although serious complications are a possibility.

Chylous Ascites: Complication of Laparoscopic Donor Nephrectomy. Case Report and Review of Literature.

BACKGROUND: Chylous ascites (CA) is an extremely rare complication after laparoscopic donor nephrectomy (LDN). It can increase the hospital stay, morbidity in postoperative period and thus negating the benefits of laparoscopic surgery. Most of the cases were managed conservatively, but surgical intervention may be occasionally required. This report describes the importance of accurate localization of the leaking chyle duct and its repair by endosuturing in a renal donor not responding to conservative treatment. METHODS: A comprehensive review of literature regarding this rare complication after LDN was performed with Pubmed/Medline and Google Scholar using "chyle," "complications," and "laparoscopic donor nephrectomy" as keywords. The demographic profile and management of patients is discussed in detail. The various surgical modalities used to manage these patients are described. RESULTS: Fifty-four cases of chyle leak/ascites have been reported after LDN in literature to date. Around 77% donors with CA could be successfully managed conservatively with dietary measures and total parenteral nutrition. Surgical intervention was required in nearly 23% donors ranging from clip application, use of argon coagulation, endosuturing with application of glue after 36.1 ± 19.07 days of failed conservative treatment. Donors with massive ascites or requiring frequent large-volume paracentesis on conservative treatment are likely to require surgical therapy. The present case was successfully managed with laparoscopic endosuturing and has no recurrence at 6 month follow-up. CONCLUSIONS: Chylous ascites is a rare complication after donor nephrectomy in experienced centers. Although conservative management remains the first line of treatment, early surgical treatment shall be undertaken in cases of massive ascites.

Ameboma of Colon Simulating Colonic Adenocarcinoma.

Amebiasis is common in tropical and developing countries with variable symptoms. Ameboma of the colon occurs rarely due to the annular growth of granulation tissue and can present as mass lesion simulating colonic carcinoma in elderly individuals. Due to diagnostic dilemma or in case of complications, for example, acute intestinal obstruction, perforation, or bleeding per rectum, the patient requires urgent surgical exploration and final diagnosis is made on histopathological examination.

Autoinhibition regulates cellular localization and actin assembly activity of the diaphanous-related formins FRLalpha and mDia1.

Diaphanous-related formins (DRFs) are key regulators of actin cytoskeletal dynamics whose in vitro actin assembly activities are thought to be regulated by autoinhibition. However, the in vivo consequences of autoinhibition and the involvement of DRFs in specific biological processes are not well understood. In this study, we show that in the DRFs FRLalpha (formin-related gene in leukocytes alpha) and mouse diaphanous 1, autoinhibition regulates a novel membrane localization activity in vivo as well as actin assembly activity in vitro. In FRLalpha, the Rho family guanosine triphosphatase Cdc42 relieves the autoinhibition of both membrane localization and biochemical actin assembly activities. FRLalpha is required for efficient Fc-gamma receptor-mediated phagocytosis and is recruited to the phagocytic cup by Cdc42. These results suggest that mutual autoinhibition of biochemical activity and cellular localization may be a general regulatory principle for DRFs and demonstrate a novel role for formins in immune function.

Specific patterns of Cdc42 activity are related to distinct elements of T cell polarization.

T cell polarization toward and within the cellular interface with an APC is critical for effective T cell activation. The Rho family GTPase Cdc42 is a central regulator of cellular polarization. Using live-cell imaging, we characterized the spatiotemporal patterns of Cdc42 activity and their physiological regulation. Using three independent means of experimental manipulation of Cdc42 activity, we established that Cdc42 is a critical regulator of T cell actin dynamics, TCR clustering, and cell cycle entry. Using quantification of three-dimensional data, we could relate distinct spatiotemporal patterns of Cdc42 activity to specific elements of T cell activation. This result suggests that Cdc42 activity in specific locations at specific times is most critical for its function in T cell activation.

Itk functions to control actin polymerization at the immune synapse through localized activation of Cdc42 and WASP.

Actin polymerization at the immune synapse is required for T cell activation and effector function; however, the relevant regulatory pathways remain poorly understood. We showed previously that binding to antigen presenting cells (APCs) induces localized activation of Cdc42 and Wiskott-Aldrich Syndrome protein (WASP) at the immune synapse. Several lines of evidence suggest that Tec kinases could interact with WASP-dependent actin regulatory processes. Since T cells from Rlk-/-, Itk-/-, and Rlk-/- x Itk-/- mice have defects in signaling and development, we asked whether Itk or Rlk function in actin polymerization at the immune synapse. We find that Itk-/- and Rlk-/- x Itk-/- T cells are defective in actin polymerization and conjugate formation in response to antigen-pulsed APCs. Itk functions downstream of the TCR, since similar defects were observed upon TCR engagement alone. Using conformation-specific probes, we show that although the recruitment of WASP and Arp2/3 complex to the immune synapse proceeds normally, the localized activation of Cdc42 and WASP is defective. Finally, we find that the defect in Cdc42 activation likely stems from a requirement for Itk in the recruitment of Vav to the immune synapse. Our results identify Itk as a key element of the pathway leading to localized actin polymerization at the immune synapse.

Synthesis of calcineurin-resistant derivatives of FK506 and selection of compensatory receptors.

We used olefin metathesis to synthesize C40 derivatives of FK506 and measured their ability, when complexed to FKBP12, to inhibit calcineurin's phosphatase activity. We identified modular dimerization domains (CABs) containing segments of the calcineurin A and B polypeptides. These CABs respond to FK506 both when overexpressed in mammalian cells and in yeast or mammalian three-hybrid assays. Using chemical genetic selection, we identified compensatory mutant CABs that respond to a calcineurin-resistant FK506 derivative at concentrations well below the response threshold for CABs containing only wild-type calcineurin sequence. These reagents provide a small molecule-protein combination orthogonal to existing dimerizer systems and may be used with existing systems to increase the complexity of induced-proximity experiments. This new use of the "bump-hole" strategy protects target cells from complications arising from the inhibition of endogenous calcineurin.